Schizophrenia was first characterized as a mental illness at the end of the nineteenth century. When the disease was initially described, it was noted that the general deterioration associated with this disease was inexorable. The variety of social, psychological, chemical, and surgical treatments and procedures tried for controlling schizophrenia at the end of the nineteen century were without positive effect.
In 1953, the introduction of neuroleptic drugs, such as chlorpromazine, into clinical practice, drastically changed the deplorable pre-existing situation concerning treatment for schizophrenia. The almost immediate ameliorative effects of these drugs heralded the new age of pharmacotherapy in psychiatry.
Neuroleptic agents or drugs (i.e. "neuroleptics"), also called anti-psychotics or major tranquilizers, remain the treatment of choice for schizophrenia, certain organic central nervous system disorders, mental illnesses, and associated psychotic processes today. Currently, it is estimated that over 95% of schizophrenics are chronically maintained on neuroleptics having pharmacological actions similar to the action of chlorpromazine, an aliphatic phenothiazine derivative which is also known generically as Thorazine.
Although the known anti-psychotic drugs have clear efficacy in the treatment of mental illness, they also have a variety of neurological side effects. The most clinically significant side effects are a host of movement disorders that are categorized based on extrapyramidal signs (EPS). Extrapyramidal signs include diverse symptoms such as Parkinsonism, akathesia, dystonia, torticollis, and oculogyric crisis. While these symptoms typically dissipate if drugs are withdrawn, psychotic relapse almost always occurs after the cessation of drug treatment. However, it has been found that pharmacological treatment with anti-cholinergic drugs is effective in treating EPS. Thus, the addition of anti-cholinergic agents such as cogentin or artane allows anti-psychotic medications to be maintained while many EPS are effectively treated.
Unfortunately, one type of EPS, a clinical manifestation called tardive dyskinesia (TD), is not amenable to any of the above-mentioned treatments. Through the years, it has become increasingly clear that a significant minority of the patients using neuroleptic drugs gradually develop TD which is a disfiguring movement disorder. Recent epidemiological studies have indicated serious rates of incidence of TD. For example, it is a conservative estimate that about 20% of all patients receiving anti-psychotic drugs and up to 70% of at-risk patients (e.g. elderly females) develop TD. The symptoms of TD most typically include involuntary movements of the facial and buccoloingual muscles. In some cases, the limbs, trunk, and even the respiratory apparatus can be affected. TD, unlike other EPS, is unresponsive to known pharmacological treatments. In addition, the severity of the symptoms of TD does not diminish with time. Indeed, the anti-cholinergic drugs which are used to alleviate other EPS syndromes actually increase the probability of inducing TD in patients treated with these drugs.
Because of its high incidence and irreversible nature, TD poses the most serious obstacle to successful pharmacotherapy for schizophrenia and some other organic central nervous system (CNS) disorders. The majority of cases of TD have been reported in patients with chronic schizophrenia, prolonged or repeated affective illness, or a variety of dementias. Importantly, however, TD also occurs in non-psychotic patients treated with neuroleptic agents for psychoneurosis, gastrointestinal disturbances, chronic pain syndromes, and personality disorders. As a consequence, strenuous efforts have been made to develop anti-psychotic drugs which do not produce TD.
To date, only one drug, clozapine, by itself possesses anti-psychotic potency and does not appear to cause TD. Unfortunately, clozapine carries a liability which has potentially more serious consequences to patients than any of the side effects associated with other conventional neuroleptics used for schizophrenia therapy. In a significant minority (e.g. at least about 2%) of all patients, clozapine leads to the development of agranulocytosis, a potentially fatal blood dyscrasia. The problem of agranulocytosis was deemed to be significant enough that, in spite of its advantages over other antipsychotic drugs, clozapine was pulled off the market after its initial introduction in Europe in the 1970's. Since the re-introduction of clozapine, weekly monitoring of blood levels is now necessary to insure the early detection of agranulocytosis. As a result of the required and continual monitoring process, the cost of clozapine treatment is prohibitive--about $6,000.00 to $9,000.00 per year per patient. This exceedingly high cost puts clozapine treatment far beyond the reach of most patients. Moreover, once a patient develops agranulocytosis from clozapine treatment, the reinstitution of therapy with this drug in surviving patients at a later time is absolutely precluded because of the almost certain recurrence of blood dyscrasia and its harmful effects. Thus, clozapine, which might be considered to be the drug of choice for treating schizophrenia, is actually a last resort.